Status: supplemental BLA approved in Sept. 2009; acquired and distributed by the U.S. government for the 2009/10 flu season.

Organizations involved:

MedImmune Inc. – Manuf.; R&D; Tech.;

World mark.

AstraZeneca plc – Parent

National Institute of Allergy and Infectious Diseases (NIAID), NIH - R&D; Tech.

National Institutes of Health (NIH) – Parent

University of Michigan - R&D; Tech.

Cross ref.: See the entry for Influenza Vaccine, live rDNA, liquid (FluMist), the seasonal influenza vaccine, with this simply a monovalent H1N1-containing analog. See the Influenza H1N1 Vaccine Products and Influenza Vaccine Products entries.

Description: Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal is an aqueous formulation of a live cold-adapted monovalent recombinant (a reassortant of 2009 virus: A/California/7/2009 (H1N1)v strain with a master recombinant influenza virus) influenza H1N1 virus vaccine for administration by intranasal spray, containing virus cultured conventionally in hen's (chicken) eggs. Like the strains in the FlulMist seasonal vaccine, the influenza virus strain in Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal is:

(a) cold-adapted (ca), i.e., it replicates efficiently at 25˚C, a temperature that is restrictive for replication of many wild-type influenza viruses);

(b) temperature-sensitive (ts) (i.e., it is restricted in replication at 39˚C, a temperature at which many wild-type influenza viruses grow efficiently); and (

c) attenuated (att), it does not produce classic influenza-like illness in the ferret model of human influenza infection.

The cumulative effect of the antigenic properties and the ca, ts, and att phenotypes is that the attenuated vaccine virus replicates in the nasopharynx to induce protective immunity. See the entry for Influenza Vaccine, live rDNA, liquid (FluMist) and the earlier frozen version of this vaccine for for further discussions.

For the reassortant virus in Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal, the six internal gene segments responsible for ca, ts, and att phenotypes are derived from a master donor virus (MDV), and the two segments that encode the two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), are derived from the corresponding antigenically relevant pandemic (H1N1) 2009 wild-type virus. Thus, the virus contained in Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal, maintains the replication characteristics and phenotypic properties of the MDV and expresses the HA and NA of the pandemic (H1N1) 2009 virus. For the MDV, at least five genetic loci in three different internal gene segments contribute to the ts and att phenotypes; five genetic loci in three gene segments control the ca property

The vaccine is packaged in prefilled intranasal sprayers contains a single 0.2 mL dose, in packages containing 10 sprayers. Each 0.2 mL dose (0.1 mL/nostril) contains 10.sup.6.5-7.5 FFU of the live attenuated influenza virus reassortant of the pandemic (H1N1) 2009 virus: A/California/7/2009 (H1N1)v. Each 0.2 mL dose also contains 0.188 mg/dose monosodium glutamate, 2.00 mg/dose hydrolyzed porcine gelatin, 2.42 mg/dose arginine, 13.68 mg/dose sucrose, 2.26 mg/dose dibasic potassium phosphate, 0.96 mg/dose monobasic potassium phosphate, and <0.015 mcg/mL gentamicin sulfate. The vaccine contains no preservatives.

The vaccine is stored at 2-8˚C (refrigerated). The cold chain (2 -8°C) must be maintained during shipping of the vaccine.

The tip attached to the sprayer is equipped with a nozzle that produces a fine mist that is primarily deposited in the nose and nasopharynx.

Manufacture: Specific pathogen-free (SPF) eggs are inoculated with the reassortant strain and incubated to allow vaccine virus replication. The allantoic fluid of these eggs is harvested, pooled and then clarified by filtration. The virus is concentrated by ultracentrifugation and diluted with stabilizing buffer to obtain the final sucrose and potassium phosphate concentrations. The viral harvests are then sterile filtered to produce monovalent bulks. Each lot is tested for ca, ts, and att phenotypes and is also tested extensively by in vitro and in vivo methods to detect adventitious agents. Monovalent bulks are diluted as required to attain the desired potency with stabilizing buffers. The bulk vaccine is then filled directly into individual sprayers for nasal administration.

Not using the influenza A/California/07/2009 (H1N1)v strain used in inactivated vaccines, MedImmune achieved expected levels of vaccine manufacture, while those culturing A/California/07/2009 (H1N1)v or wild strains experienced difficulties in propagating the virus to sufficient titers (took longer than expected).

Companies.: The vaccine was developed and is manufactured and marketed in the U.S. by MedImmune, Inc., CBER/FDA est. no. 1799. MedImmune is a subsidiary of AstraZeneca plc, which handles international marketing.

In May and June 2009, MedImmune received orders from BARDA/NIAID/NIH (HHS; federal government) for 13 million doses, and in Sept. 40 received an order for an additional 29 million doses. Thus, the federal government purchased ~42 million doses costing a total of $453 million.

Manufacture: One exception to these vaccine-productivity problems is the MedImmune H1N1 flu vaccine, which is a liveattenuated vaccine, says Raburn Mallory of the Gaithersburg, Md.-based company, which is a subsidiary of AstraZeneca in London, U.K. This vaccine, which is delivered to individuals intranasally, is being produced with "good yields" that are "much like" those for the company's live-attenuated seasonal flu vaccine, he says.

Approvals: Date = 20090915; sBLA (BL 125020/1215)

Indications: [full text of the "Indications and USAGE" section of product insert/labeling]:

Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal is indicated for the active immunization of individuals 2-49 years of age against influenza disease caused by pandemic (H1N1) 2009 virus.

Status: On Sept. 15, 2009, FDA granted a supplemental BLA for this H1N1 vaccine.

Tech. transfer: See the FluMist entry for patents and licensing.

Trials: As of Oct. 2009, clinical studies were ongoing to determine the optimal number of doses.

Medical: Available data show (in Oct. 2009) that children 9 years of age and younger are largely serologically naïve to the pandemic (H1N1) 2009 virus, i.e., they have never been exposed and have no protective antibodies/immunity. The vaccine should be administered as follows:

Children age 2 years through 9 years, 2 doses (0.2 mL each, 0.1 mL per nostril, approximately 1 month apart)

Children, adolescents and adults age 10 through 49 years, 1 dose (0.2 mL), 0.1 mL per nostril

Because it is live and stimulates a broad range of immune responses, H1N1 LAIV may offer some cross-protection against circulating flu strains that have "drifted" - that are very closely-related but not perfectly matched to the flu strains in the vaccine.

Market: For 2009 (2009/10 flu season), the author crudely estimating that, besides $450 million (about $10.70/dose) in sales to the U.S. government (discussed in the Companies section), MedImmune's sales ($ not units) through commercial venues will comparable. Thus, total sales may be on the order of $900 million.

The typical cost per dose for the H1N1 vaccine is "a little less" than the cost per dose of the company's seasonal flu vaccine, FluMist (see related entry). The H1N1 vaccine would be expected to cost less, since it is mono- rather than trivalent.